4-850940-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005255.4(GAK):c.3653T>G(p.Leu1218Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,612,172 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (15 hom.)
• Consequence: GAK NM_005255.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.11

Genes affected

GAK (HGNC:4113): (cyclin G associated kinase) In all eukaryotes, the cell cycle is governed by cyclin-dependent protein kinases (CDKs), whose activities are regulated by cyclins and CDK inhibitors in a diverse array of mechanisms that involve the control of phosphorylation and dephosphorylation of Ser, Thr or Tyr residues. Cyclins are molecules that possess a consensus domain called the 'cyclin box.' In mammalian cells, 9 cyclin species have been identified, and they are referred to as cyclins A through I. Cyclin G is a direct transcriptional target of the p53 tumor suppressor gene product and thus functions downstream of p53. GAK is an association partner of cyclin G and CDK5. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008222342).
• BP6: Variant 4-850940-A-C is Benign according to our data. Variant chr4-850940-A-C is described in ClinVar as [Benign]. Clinvar id is 720325.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00605 (921/152178) while in subpopulation AFR AF= 0.0211 (877/41532). AF 95% confidence interval is 0.02. There are 11 homozygotes in gnomad4. There are 422 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 922 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAK	NM_005255.4	c.3653T>G	p.Leu1218Arg	missense_variant	26/28	ENST00000314167.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAK	ENST00000314167.9	c.3653T>G	p.Leu1218Arg	missense_variant	26/28	1	NM_005255.4	P1

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 922 AN: 152060 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00170 AC: 426 AN: 250762 Hom.: 12 AF XY: 0.00120 AC XY: 163 AN XY: 135578

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000629 AC: 918 AN: 1459994 Hom.: 15 Cov.: 30 AF XY: 0.000512 AC XY: 372 AN XY: 726200

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00605 AC: 921 AN: 152178 Hom.: 11 Cov.: 32 AF XY: 0.00567 AC XY: 422 AN XY: 74398

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.00687

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00213 AC: 258

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0082	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.2	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.4	D;D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.90	P;.;.
Vest4		0.81
MVP		0.46
MPC		0.60
ClinPred		0.059	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150598346; hg19: chr4-844728;